A central role for serum lipids in the pathogenesis of vascular disease has long been postulated, but has remained an illusive problem for both the biochemist and the clinician. Recent epidemiological investigations have importantly implicated plasma low density lipoprotein (LDL) as enhancing the atherogenic process, with high-density lipoprotein (HDL) potentially reducing the atherogenic potential. The present investigation has posed two linking hypothesis from the last 10 years of investigation into the metabolism of lipoproteins and their relationship to carbohydrate physiology: 1) Abnormalities of metabolism of the apoprotein moieties associated with circulating lipoproteins may be central to the pathophysiology of excess LDL:HDL relationships. 2) An hormonal basis for lipoprotein-apoprotein regulation with a relative excess of insulin and/or deficiency of glucagon may represent the initiating or maintaining events which alter carrier protein metabolism. If this sequence of events represents the mechanism and pathophysiology of some forms of human lipoprotein disease, then the implications in terms of diagnosis and therapy are clear. Finally, the utilization of a genetic model of human Type IV hyperlipemia (Zucker Rat) in our investigation of both apoprotein regulation and pharmacologic response provides an unusual animal model with which to examine hypotheses suggested by both our research and those of other investigators in the field.